Cluster randomized trial of influenza vaccination in patients with acute heart failure in China: A mixed-methods feasibility study

Uncertainties about the efficacy of influenza vaccination for populations with heart failure (HF) in preventing cardiovascular outcomes, as well as lack of effective vaccination strategies, may contribute to low vaccine coverage rate (VCR) in China and globally. We assessed the feasibility of a strategy to promote influenza vaccines in patients hospitalized with acute HF in China and to inform the design of a hybrid effectiveness-implementation cluster randomized trial to evaluate this strategy on mortality and hospital re-admission. We conducted a cluster randomized pilot trial involving 11 hospitals in Henan Province in China, with mixed-methods evaluation between December 2020 and April 2021. A process evaluation involved interviews with 51 key informants (patients, health professionals, policy makers). The intervention included education about influenza vaccination and availability of free vaccines administered prior to hospital discharge for HF patients, while usual care included attending community-based points of vaccination (PoV) for screening and vaccination. Implementation outcomes focused on reach, fidelity, adoption, and acceptability. Recruitment rates were assessed for trial feasibility. Effectiveness outcomes were influenza VCR, HF-specific rehospitalizations and mortality at 90 days. A total of 518 HF patients were recruited from 7 intervention and 4 usual care hospitals (mean of 45 participants per hospital per month). VCR was 89.9% (311/346, 86.1–92.8%) in the intervention group and 0.6% (1/172, 0.0–3.7%) in the control group. The process evaluation demonstrated reach to patients with lower socioeconomic and education status. There was good fidelity of the intervention components, with education and PoV set up processes being adapted to local hospital workflow and workforce capacity. Intervention was acceptable and adopted by patients and health professionals. However, outside of a trial setting, concerns were raised around vaccination reimbursement costs, workforce accountability and capacity. The intervention strategy appears feasible and acceptable for improving VCR in HF patients at county-level hospitals in China. Trial registration: This pilot trial is registered with the acronym PANDA II Pilot (Population Assessment of Influenza and Disease Activity) at ChiCTR.org.cn (ChiCTR2000039081).


Protocol Synopsis
Title (Population Assessment of iNfluenza and Disease Activities, PANDA II pilot)

Rationale
Considerable data support the broad benefits of influenza vaccination in the general population. However, there is uncertainty over the effectiveness of influenza vaccination in preventing cardiovascular events in the high-risk population such as those with HF. Influenza vaccination is not covered by medical insurance in majority of China. The rate of influenza vaccination was as low as 0.6% in Chinese patients with HF, compared to about 60% in the Western European countries and in the US. Thus, it is of critical importance to detect whether providing free influenza vaccine, providing vaccination service in hospital, and educating patients as well as health provider will increase vaccine rate among patients hospitalized due to severe symptoms of HF. If so, whether improved influenza vaccine rates in patients with HF will reduced all-cause death or HF hospitalization. Before a definitive randomized cluster randomized trial, a pilot study is planned to address the following uncertainties for the design of future definitive study: (i) Whether the intervention package is feasible; (ii) Whether a target influenza vaccine rate of 90% is achievable in the intervention clusters; (iii) Proportion of patients hospitalized with HF getting influenza vaccination in routine care; (iv) Number of patients will be enrolled in future study.

Study design
Two-arm, parallel, hospital-based, cluster randomized trial.

Intervention
(i) education of the health care team and patients; (ii) provision of free vaccine on the day of discharge; and (iii) provision of immunization service inside hospital before discharge.

Number of participants
330 patients; recruitment from 11 hospitals in one influenza season (average of 30 patients per hospital).

Study duration 12 months
Endpoints/Outcomes Primary outcomes: influenza vaccine coverage rate (VCR) in both groups. Secondary outcomes: number of patients recruited during study period, rate of patient follow-up, death or readmission for HF over 3 months follow-up.

Site inclusion criteria
• Capable of admitting, treating, recruiting HF patients; • With the capacity of treating >35 HF patients per month during recruitment period; • Staff with available care team personnel to collaborate and control the lost to follow-up rate to <10%. • Local approval to provide influenza vaccination from administrative bureau.

Site exclusion criteria
• Participating in vaccination-related or other HF patient outcome improvement programs that might confound study outcomes.

Patient inclusion criteria
• All adult inpatients (age ≥18 years) discharged with a diagnosis of HF during recruitment month in participating hospital; • Assessed as New York Heart Association (NYHA) III-IV during hospitalization; • Consent to participate in the study.

Patient exclusion criteria
• Known allergy to influenza vaccine; • Pregnant women.

Intervention administration
Staff of the participating hospitals.

Safety evaluation
Adverse Event Following Immunization (AEFI) will be monitored and reported.

Study schedule
Pilot phase December 1, 2020 -November 30, 2021. Each patient will be followed for 3 months.

Statistical considerations
Rates of influenza vaccination (the number of patients received influenza vaccine divided by the number of patients enrolled in the intervention group and in the control group, will be reported respectively. Number of patients enrolled in both the intervention and the control group will be reported. Rate of patient follow-up at 3 months after enrollment will be reported.

Data Management
A web-based electronic data capture system will be used to store and check data.

Background
Heart failure (HF) is a major clinical and public health concern. An estimated 1.3% (13.7 million) of the adult population (age ≥35 years) have HF in China. 1 Burden of hospitalizations and health care costs among individuals with HF in China are higher than those in other low and middle income countries. 2 About one-third of HF associated hospitalizations are triggered by respiratory infection. 3,4 Considerable data support the broad benefits of influenza vaccination in the general population. 5 However, there is uncertainty over the efficacy of influenza vaccination for preventing cardiovascular events in the high-risk patients with HF. 6,7 Although Guidelines for HF management and guidelines for other cardiovascular disease management recommend influenza vaccine for patients with cardiovascular disease, there are scare of evidence-based data as to the effect of influenza vaccination in patients with HF.
Associations between influenza and cardiovascular disease varied from study to study. In a retrospective cohort, for patients with existing congestive heart failure (CHF), the overall hospitalization rate during influenza season was 11% higher (Hazard Ratio [HR] 1.11, 95% confidence interval [CI] 1.03-1.20) than that during non-influenza season. 8 A population-level estimate of influenza-associated excess cardiovascular hospitalization accounted for 10% (95% CI, 7%-14%) in the oldest old. 9 However, all-cause hospitalization wasn't found to be associated with influenza vaccination in HF patients in a post hoc analysis of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study. This secondary analysis from trial data showed influenza vaccination was associated with lower risk of all-cause death (HR 0.82, 95% CI 0.70-0.96), but not with lower risk of cardiovascular death or HF-related hospitalization, or all-cause hospitalization. 10 11 However, a data linkage study from the Get With The Guidelines -Heart Failure (GWTG-HF) quality improvement initiative showed similar 1-year all-cause mortality and 1-year all-cause readmission between influenza vaccinated HF inpatients and those unvaccinated. 12 Given the above inconsistent results observed in different studies, definitive conclusions cannot be drawn without high quality randomized clinical trials.
Influenza vaccination is more commonly reimbursed for both the elderly and those with chronic conditions by public funding in the Americas and the Western Europe than in the Western Pacific. 13,14 A government run insurance scheme for influenza vaccines seems correlates more with a higher influenza vaccine coverage rate, than with economic development status across countries. 15 In China, the free influenza vaccine policy for people older than 60 years old is only applied in a few cities. 16 The rate of influenza vaccination was as low as 0.6% in Chinese patients with HF, compared to about 60% in the Western European countries and in the US. 10 Given the WHO recommendation that all people except those younger than 6 months should get influenza vaccine, the low influenza vaccine rate in China provides us a chance to study the efficacy of influenza vaccination in reducing mortality and HF hospitalization, as neglectable low proportion of HF patients received the influenza vaccine in the routine care.
Under current vaccine regulations in China, adult immunization service can only be sought at licensed community health center or immunization clinics housed in center for disease control and prevention (CDC). Hospitals are allowed to establish a temporary Point of Vaccination (POV) after a quality check and then approval valid for three months from their local department of health. But most hospitals don't have a POV in place at the time as many of them consider vaccination being out of the scope of clinical services. Unaware of the importance of annual vaccinations, not knowing where to get vaccinated, and not wanting to pay are the top barriers prohibiting those with chronic conditions from getting influenza vaccines. 17 Thus, it is of critical importance to investigate whether improved influenza vaccine coverage rate in patients with HF will reduced all-cause death or HF hospitalization. Before investigating the efficacy of influenza vaccines on preventing cardiovascular disease, we need to first address whether educating patients and health provider, providing vaccination service in hospital, and providing free influenza vaccine will achieve a target vaccine coverage rate (VCR) among patients hospitalized due to severe symptoms of HF.
Before a definitive cluster randomized trial, a pilot feasibility study is planned to address the following uncertainties: 1) Whether the intervention package is feasible; 2) Whether a target influenza vaccine rate of 90% is achievable in the intervention clusters; 3) Proportion of patients hospitalized with HF getting influenza vaccination in routine care; 4) Number of patients will be enrolled in future study.

Methods
This protocol follows the extension to CONSORT 2010 statement on reporting pilot and feasibility trials, the SPIRIT 2013 statement on standard protocol items for clinical trials, and its explanation and elaboration report. [19][20][21] Trial design This pilot trial is a two-arm, parallel, hospital-based, cluster randomized trial where 7 hospitals will be randomized to intervention and 4 hospitals to control arm. All eligible HF inpatients from each hospital will be recruited during 2020 November. Intervention includes (i) education of the health care team and patients; (ii) provision of free vaccine on the day of discharge; and (iii) provision of immunization service inside hospital before discharge.

Setting
PANDA II pilot will be conducted in county-level hospitals in Henan Province, China. County-level hospitals serve a relatively fixed population living in the corresponding geographic area, which to the largest extent prevents recruiting the same patients seeking care in different participating centers.
Inclusion criteria for participating sites: 1) capable of admitting and treating HF patients; 2) with the capacity of treating >35 HF patients per month during recruitment period; 3) staff with available care team personnel to collaborate. 4) local approval to provide influenza vaccination from administrative bureau/ center for disease control and prevention (CDC).
Exclusion criteria for participating sites: Participation in a vaccination-related HF patient outcome improvement programs that might confound study outcomes.

Patients
PANDA II pilot trial will focus on HF patients at higher risk of having serious complications from influenza infection. HF is largely a clinical diagnosis. Based on the widely used Boston criteria, HF will be defined according to the attending physician's report of any of the following clinical symptoms described as dyspnea ('unusual' on light exertion or recurrent in the supine position); fluid retention; description of 'rales' in the lungs, jugular venous distension, or pulmonary edema on physical examination; or pulmonary edema on chest x-ray presumed related to cardiac dysfunction. 22 HF patients will be identified through screening the admission list of a cardiovascular ward in each participating hospital for the following eligibility criteria.
Inclusion criteria for participating patients: 1) all the adult inpatients (age ≥18 years) with a discharge diagnosis of HF during recruitment month in participating hospitals; 2) assessed as New York Heart Association (NYHA) function classification III-IV during hospitalization; 3) consent to participate in the study.
Exclusion criteria for participating patients: 1) have known allergy to influenza vaccine.

Intervention
The intervention will include three components: 1) education to all members of the health care team, physicians, nurses, and patients; a. A 30-minute training session to health care teams in all participating hospitals after they are included in the study. Members in a health care team include site investigators, physicians, and nurses. The training session include the association between influenza vaccine and lower risk of mortality and rehospitalization in patients with HF, the study protocol, and current regulations on vaccine circulates. The education material will be designed and delivered by study investigators. b. Study nurses in each participating hospital will lead a 15-minute group or individual training session to patients after they reach a relative-stable status during hospitalization. The training sessions include plain language version content on association between influenza infection and cardiovascular disease and current guideline recommendations of influenza vaccine for secondary prevention in patients with established cardiovascular disease. The training material (presentation slides, scripts, and videos) will be designed and delivered by study investigator. 2) provision of free influenza vaccine on the day of discharge; 3) provision of immunization service inside hospital before discharge and a minimum of 1 hour after vaccination and before discharge to observe any potential adverse events of the vaccination.

Comparator
Currently the routine practice is that HF patients discharged from hospitals seek and pay for influenza vaccination service in community health center or immunization clinic at local CDC.

Primary outcome
• Rate of uptake of influenza vaccination among eligible patients in the intervention hospitals and that in the control hospitals; • Number of patient recruited; • Rate of adherence to follow-up;

Secondary outcome
• Influenza-like illness (ILI) rate; influenza-like illness is defined as an acute respiratory illness with a measured temperature of ≥ 38 °C and cough, within the past 10 days. 23 • Death or readmission for heart failure rate over 3 months follow-up through faceto-face or phone call follow-up.

Participant timeline
This pilot study will be conducted between December 2020 and November 2021. Participating centers and participants will be recruited in December 2020. Both hospitals and patients will go through their eligibility screening respectively. Eligible hospitals and patients will then be informed about the study, potential benefits and risks, and be asked for consent. Consented hospitals will be randomized into intervention or control arm before the commencement of the study. Eligible patients will be assessed through collecting their baseline demographics, disease history, and clinical characteristics during hospitalization. On the day of discharge, eligible patients in intervention hospitals will receive influenza vaccine shots. Face-to-face follow-up visits for each patient will be scheduled at 1-month and 3-month post discharge. Study outcome data will be collected during the follow-up visits. If the patient is unable to return for such a visit, they will receive a telephone call instead.

Sample size
As this is a pilot trial and the primary objective is to test the feasibility of increasing influenza vaccination uptake in HF patients, other than to test the efficacy or effectiveness of intervention, a practical number of 11 participating sites and inpatients with HF during one month (30 patients on average) from each site are set. Intra-cluster correlation coefficient of 3-month death or rehospitalization due to heart failure will be calculated using the outcome of each individual from each cluster. 24

Recruitment
An estimated average of 30 patients per hospital will be set for recruitment. The admission list from each participating site will be monitored to ensure recruiting consecutive heart failure patients to prevent potential selection bias. If a quota of 50 patients is reached in any given hospital, the recruitment process will end.

Data collection methods
Case report forms (CRFs) at screening, baseline, admission, intervention, vaccination, discharge, 1-month and 3-month follow-up will be designed to collect patient characteristics and study outcomes. Data will be assessed by site investigator team and sampled by steering committee. Outcome data will also be collected for patients who drop out of or drop in to the intervention.

Data Management
An electronic data capture (EDC) system with automatic range checks will be used for data entry and storage. Double entry will be applied to assure data quality.

Sequence generation
In this pilot cluster randomized trial, randomization will be applied to participating sites. Computer-generated random numbers for 11 hospitals with 7 in the intervention arm and 4 in the control arm. Site investigators will enroll participants. All eligible patients in intervention hospitals will receive influenza vaccines.

Blinding
This is an open label study.

Analysis
Descriptive analysis will include VCR, number of recruitment, ILI rate and 3-month death or HF readmission in intervention and control hospitals. Clustering effect will be considered when using individual-level data. The proportion of each outcome measure and its confidence interval will be calculated. Analysis will be done at the end of recruitment and the end of follow-up. All statistical analyses will be undertaken using R 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria, https://www.Rproject.org/). Schedule of PANDA II pilot is in Figure 1.

Data monitoring
We plan to use a combination of central (remote) and site monitoring of the accumulating data. Prior to the initiation of the study at any participating center, all designated research staff will be trained on the study procedures by the operational staff. Data collected by research nurse/coordinator should be monitored and verified every day by operational staff. Mistakes found need to be corrected in time. An independent Data Safety Monitoring Board (DSMB) will meet every month to review the data quality.

Harms
Every patient in this trail will be insured by a contracted insurer. Adverse Event Following Immunization (AEFI) will be reported to steering committee and the manufacturer pharmacovigilance team. AEFI include vaccine product-related reaction, vaccine quality defect-related reaction, immunization error-related reaction, immunization anxiety-related reaction, and coincidental event. Trial insurer and/or vaccine manufacturer will compensate to those who suffer harm from severe AEFI.

Audit
DSMB will audit the trial conduct during the meeting every six month.

Protocol amendment
We plan to communicate important protocol modifications (e.g. changes to eligibility criteria, outcomes, analyses) to relevant parties (e.g. Investigators, ERC/IRBs, trial participants, trial registries, journals, regulators) on investigators meeting every other week.

Consent
In this pilot cluster randomized trial, we plan to obtain the informed consent from each participating site and each individual participant. Informed consent can only be signed if the patient or designated proxy is fully aware of the risks and possible outcomes.

Confidentiality
Personal information about potential and enrolled participants will be collected, shared and maintained by trial staff in order to protect confidentiality before, during and after the trial. The whole process of data collecting and analyzing will be conducted anonymously.

Declaration of interest
This study will be supported by Sanofi Pasteur.

Access to data
The principal investigator will have full access to study data. A data analytical plan is required if intending to apply for data access.

Dissemination policy
The final conclusion of this pilot trail will be released to public through academic conferences, journals or mass media. The release decision will be made by the study steering committee.

Funding
This study will be supported by Sanofi Pasteur (study code: FLU00144).